Gastric Acid Medications

Gastric acid medications include proton pump inhibitors (PPIs) and H₂ receptor antagonists (also known as H₂ blockers). The drugs work through different mechanisms to suppress acid secretion by parietal cells in the stomach. The most common indications include peptic ulcer disease, GERD, and dyspepsia. Adverse effects of PPIs include malabsorption, acute interstitial nephritis, and an increased risk of Clostridioides difficile infection. Adverse effects of H₂ blockers include CNS effects, bradycardia/hypotension, gynecomastia, and galactorrhea. Both classes are associated with drug interactions related to the cytochrome P450 system.

Last update:

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Overview

Physiology of acid secretion

Parietal cells are located in the body of the stomach and secrete hydrochloric acid (HCl) into the lumen.

  • Water and CO₂ are combined to produce hydrogen (H+) ions and HCO₃ ions by the action of the carbonic anhydrase enzyme.
  • H+ is transported to the lumen of the stomach via the H+/K+ ATPase pump.
  • HCO₃ is exchanged for chloride (Cl) ion.
  • H+ and Cl combine to form the final product: HCl
Ion transport in parietal cells

Ion transport in parietal cells:
Carbonic acid disassociates into a hydrogen (H+) ion and bicarbonate (HCO3). The H+ is exchanged for potassium (K+) in the apical membrane by the H+/K+ ATPase. Bicarbonate is exchanged for chloride (Cl) in the basolateral membrane, which then moves into the lumen. The Na+/K+ ATPase pump in the basolateral membrane creates the cell’s electrochemical gradient.

Image by Lecturio.

Receptors and regulation

Acid production is stimulated by:

  • Acetylcholine → muscarinic receptors
  • Histamine release by enterochromaffin-like (ECL) cells → H₂ receptors
  • Gastrin release by gastrin cells → cholecystokinin-2/cholecystokinin-B receptors

Drug classes

Common medication classes used to control gastric acid secretion include:

  • Proton pump inhibitors (PPIs)
  • H₂ receptor antagonists

PPIs

Definition

Proton pump inhibitors are a group of drugs irreversibly inhibiting the H+/K+ ATPase pump in gastric parietal cells.

Chemistry

  • Composed of 2 moieties: 
    • Benzimidazole
    • Pyridine
  • Weak bases
  • Includes:
    • Omeprazole
    • Lansoprazole
    • Pantoprazole
    • Rabeprazole

Mechanism of action

  • Administered as a prodrug → concentrated in secretory canaliculi of the parietal cell
  • Converted to an active form (a sulfonamide cation) → covalently binds to the H+/K+ ATPase pump
  • Causes irreversible inhibition → prevents movement of H+ into the gastric lumen → ↓ acid secretion
  • Inhibits both basal acid output and meal-stimulated output
Acid secretion

Mechanism of action of proton pump inhibitors (PPIs):
The drugs accumulate in the gland lumen, convert to the active form, and covalently bond to the H+/K+ ATPase, which results in irreversible inactivation and reduced acid secretion.

Image by Lecturio.

Pharmacokinetics

Absorption:

  • The most common route of administration is oral, but the medications can also be given intravenously.
  • Inactive prodrugs
  • Acid labile → formulated as acid-resistant, enteric-coated tablets or capsules
  • Pass through the stomach → absorbed in the alkaline intestinal lumen
  • Bioavailability is ↓ by the presence of food and should be administered 30–60 minutes prior to food intake.

Distribution:

  • Lipophilic 
  • Readily cross into acidified areas (e.g., the lumen of the parietal cell gland)
  • The serum half-life is short (called “hit-and-run” drugs because the duration of action is prolonged by approximately 24 hours).
  • 3–4 days for maximum effect

Metabolism: 

  • Rapid, hepatic 1st-pass metabolism
  • Cytochrome P450 enzymes:
    • CYP2C19
    • CYP3A4
  • Dose reduction is required in severe liver disease.

Excretion: 

  • Renal (primary)
  • Feces

Adverse effects

  • General:
    • Diarrhea
    • Headache
    • Abdominal pain
  • Nutritional side effects on prolonged therapy:
    • Malabsorption of vitamin B12
    • ↓ Calcium absorption → ↑ risk of fracture in elderly
    • Iron deficiency
    • Hypomagnesemia
  • ↑ Risk of infection:
    • Clostridioides difficile
    • Bacterial gastroenteritis
    • Community-acquired and nosocomial pneumonia
  • Gastrointestinal: 
    • Microscopic colitis
    • Hypergastrinemia
    • Atrophic gastritis
  • Other:
    • Acute interstitial nephritis
    • Drug-induced lupus

Drug interactions

  • Interactions due to CYP450 enzymes:
    • ↓ Activity:
      • Clopidogrel requires CYP219 for action → concurrent use of PPI can ↓ anticoagulant and antiplatelet action
      • Theophylline
    • PPIs inhibit the metabolism of:
      • Warfarin
      • Diazepam
      • Phenytoin 
  • ↓ Gastric acidity can alter the absorption of medications:
    • Ketoconazole
    • Amphetamines (e.g., dextroamphetamine)

H₂ Receptor Antagonists

Definition

H₂ receptor antagonists (also known as H₂ blockers) are competitive inhibitors of H₂ receptors in parietal cells, which aid in the reduction of acid secretion.

Chemistry

  • Histamine-based molecules
  • Includes: 
    • Famotidine
    • Cimetidine
    • Nizatidine 
    • Ranitidine (withdrawn from the market in the United States in 2020)

Mechanism of action

  • Competitive, reversible antagonists of H2 receptors on gastric parietal cells:
    • Histamine is blocked from binding to the receptor → ↓ cAMP → ↓ protein kinase activation 
    • ↓ Activation of H+/K+ ATPase → ↓ acid secretion
    • Additional consequence: ↓ effect of acetylcholine and gastrin on parietal cells
  • ↓ Basal output and meal-stimulated output
Mechanism of action for H2 receptor antagonists

Mechanism of action for H2 receptor antagonists (H2 blockers):
The antihistamine effect blocks the activation of H+/K+ ATPase through the cAMP-dependent pathway, resulting in decreased acid secretion.

Image by Lecturio.

Pharmacokinetics

  • Absorption:
    • Given in oral and IV preparations
    • Well absorbed
    • Not affected by food
  • Distribution:
    • Onset of action: 30–60 minutes
    • Half-life range: 1–4 hours
    • The volume of distribution decreases in the elderly.
    • Crosses the placenta and is secreted in breast milk
  • Metabolism:
    • Hepatic 1st-pass metabolism
    • Some are metabolized by the cytochrome P450 system.
  • Elimination: renal 

Indications

  • GERD
  • Dyspepsia
  • Peptic ulcer disease (PUD)
  • Stress-ulcer prophylaxis
  • Prevention of aspiration pneumonia
  • Anaphylaxis (in combination therapy)

Adverse drug reactions

  • General: 
    • Diarrhea
    • Headache
    • Fatigue
  • CNS effects (associated with IV administration): 
    • Confusion
    • Hallucinations
    • Agitation
  • Cardiovascular (associated with rapid IV administration):
    • Bradycardia
    • Hypotension
  • Reproductive effects (cimetidine-related): 
    • Gynecomastia
    • Impotence in men
    • Galactorrhea in women 
  • Other:
    • Vitamin B12 deficiency (with long-term use)
    • Myelosuppression

Interactions

The medications can be potent inhibitors of cytochrome P450 (particularly cimetidine), resulting in ↑ plasma concentrations of:

  • Warfarin
  • Theophylline
  • Carbamazepine
  • Tacrolimus
  • Statins
  • Many other drugs

References

  1. Katzung, Bertram G., and Trevor, Anthony J., editors. Basic & Clinical Pharmacology. 13. ed, McGraw-Hill Education, 2015.
  2. Hilal-Dandan, Randa, et al. Goodman and Gilman’s Manual of Pharmacology and Therapeutics. 2014. Open WorldCat, http://accesspharmacy.mhmedical.com/book.aspx?bookid=1810
  3. Le, Tao, et al. First Aid for the USMLE Step 1 2020. 2020. Open WorldCat, https://mhebooklibrary.com/doi/book/10.1036/9781260462050
  4. Vakil N.B. (2020). Peptic ulcer disease: Treatment and secondary prevention. Retrieved 27 November 2020, from https://www.uptodate.com/contents/peptic-ulcer-disease-treatment-and-secondary-prevention
  5. Vakil N.B. (2020). Peptic ulcer disease: Epidemiology, etiology, and pathogenesis. Retrieved 27 November 2020, from https://www.uptodate.com/contents/peptic-ulcer-disease-epidemiology-etiology-and-pathogenesis
  6. Wolfe, M.M. (2020). Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid-related disorders. In Grover, S. (Ed.), UpToDate. Retrieved July 16, 2021, from https://www.uptodate.com/contents/proton-pump-inhibitors-overview-of-use-and-adverse-effects-in-the-treatment-of-acid-related-disorders
  7. Vakil, N.B. (2020). Antiulcer medications: Mechanism of action, pharmacology, and side effects. In Grover, S. (Ed.), UpToDate. Retrieved July 16, 2021, from https://www.uptodate.com/contents/antiulcer-medications-mechanism-of-action-pharmacology-and-side-effects
  8. Costanzo L. (2018). Physiology. Philadelphia: Mosby Elsevier
  9. “List of Proton Pump Inhibitors + Uses, Side Effects.” Drugs.com, https://www.drugs.com/drug-class/proton-pump-inhibitors.html
  10. Vakil, N. (2021). Drug treatment of gastric acidity. [online] MSD Manual Professional Version. Retrieved July 16, 2021, from https://www.msdmanuals.com/professional/gastrointestinal-disorders/gastritis-and-peptic-ulcer-disease/drug-treatment-of-gastric-acidity

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details